The present invention generally relates to the preparation of pyrazoles. In one embodiment, the present invention relates to a process for the formation of a 1-(4-sulfonylphenyl)pyrazole from the condensation of diketones and hydrazines.
Pyrazoles have been widely described as pharmaceutical therapeutic agents, including anti-inflammatories and antidiabetics. In particular, [3-haloalkyl-1H-pyrazole-1-yl]benzenesulfonamides have been used as potent antiinflammatories without the side effects commonly associated with previous anti-inflammatory agents.
The preparation of pyrazoles from the condensation of diketones and hydrazines has previously been reported. See, for example, European Patent No. 418,845, European Patent No. 554,829, T. Nishiwaki, Bull. Chem. Soc. Japan, 42, 3024-26 (1969); J. Wright et al., J. Med. Chem., 7, 102-5 (1963); and R. Soliman and H. Feid-Allah, J. Pharm. Sci., 70, 602-5 (1980). These methods, however, have been criticized as not providing a scalable commercial process.
In WO 00/42021, O'Shea et al. describe a two step process for the preparation of pyrazoles from the condensation, in an amide solvent, of a diketone and a hydrazine. The pyrazole is produced as a solvate of the amide solvent and is then isolated and recrystallized from isopropanol and water to produce an unsolvated pyrazole. Disadvantageously, however, the diketone is isolated prior to the condensation reaction with hydrazine, a multi-solvent system is used, more than one crystallization is required, and the payload is relatively low.
In U.S. Pat. Nos. 5,892,053 and 5,910,597, Zhi et al. describe a scalable two step process for the preparation of pyrazoles from the condensation of diketones and hydrazines. In the first step, a diketone is formed by the treatment of a ketone with base and ester in a suitable solvent. In the second step, the diketone is solubilized in an aqueous alcohol and condensed with a hydrazine to form the pyrazole product. This two step process has been used on a commercial scale for the preparation of celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzenesulfonamide) sold under the trademark CELEBREX® by Pharmacia Corporation as shown in the following reaction:
While this synthetic approach proceeds with high selectivity to celecoxib, about 2-5 wt. % of regioisomer and hydroxyregioisomer by-products are formed under commercial conditions.

The regioisomer and hydroxyregioisomer by-products must be separated from celecoxib in a purification step to enable the celecoxib to meet purity requirements. The separation is typically done through a crystallization step in which celecoxib preferentially crystallizes while the regioisomer and hydroxyregioisomer by-products predominantly remain in solution. The celecoxib crystals are then removed from the resultant slurry and separated from impurities by solid-liquid separation techniques known to those skilled in the art, such as centrifugation or filtration.
Under commercial conditions used to date, of the two by-products, regioisomer is selectively formed over hydroxyregioisomer. This is problematic, however, since the regioisomer is generally more difficult to separate through crystallization from celecoxib than is the hydroxyregioisomer, and regioisomer concentrations of greater than about 1% typically require two crystallizations to achieve desired celecoxib purity. The second crystallization adds time to the manufacturing process and thus negatively impacts product throughput. Additionally, a second crystallization reduces yield as some celecoxib remains uncrystallized and is not recovered from the liquid phase.